Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell neoplasms that occur in patients with neurofibromatosis type 1 (NF1), the most common genetic disease affecting the nervous system. Nf1 and p53 tumor suppressor gene mutations occur commonly in MPNSTs and epigenetic factors such as stimulation by growth factors likely cooperate with these mutations to promote MPNST tumorigenesis. We hypothesized that proteins in the neuregulin-1 (NRG-1) family of growth and differentiation factors promote MPNST tumorigenesis. To test this hypothesis, we generated transgenic mice expressing the NRG-1 isoform glial growth factor-(3 (GGF133) in Schwann cells (P0-GGF(3 mice). P0-GGF(3 mice demonstrate prominent Schwann cell hyperplasia, preneoplastic lesions in peripheral ganglia and MPNST-like Schwann cell neoplasms. Our preliminary studies of MPNSTs arising in P0-GGF(3 mice indicate that neurofibromin, the product of the Nf1 gene, is not expressed in these neoplasms and that their p53 expression is also altered. Human MPNSTs likewise co express multiple NRG-1 isoforms and erbB receptors and we have found that the proliferation of 2 human MPNST cell lines is dependent on erbB signaling. As MPNST formation in P0-GGF(3 mice results from altered growth factor expression, these mice represent a transgenic model distinct from all others previously described and provide a unique opportunity to examine interactions between epigenetic factors and tumor suppressors during in vivo MPNST formation. In this proposal, we will partner the P0-GGF(3 mouse model with mouse and human MPNST cell lines to critically test the hypothesis that constitutive activation of the NRG-1/erbB signaling pathway and mutations of the Nf1 and p53 tumor suppressor genes cooperate to promote MPNST pathogenesis. Specifically, we will test the hypotheses that: 1) Specific NRG-1 isoforms and erbB membrane tyrosine kinases are individually necessary for MPNST proliferation, survival and/or migration in vitro and that constitutive activation of the NRG-1/erbB signaling pathway is necessary for MPNST tumorigenesis in vivo; 2) loss of NJ7 and p53 tumor suppressor gene function is associated with MPNST tumorigenesis in P0-GGF(3 mice and 3) constitutive activation of the NRG-1/erbB signaling pathway and null mutations of the Nf1 and/or p53 tumor suppressor genes cooperate to accelerate MPNST tumorigenesis in vivo. These studies will provide important insights into the mechanisms promoting MPNST formation and establish the NRG-1/erbB signaling pathway as a novel therapeutic target in MPNSTs. [unreadable] [unreadable]